Mucormycosis, most commonly caused by Rhizopus oryzae, is a life-threatening infection that occurs in patients immunocompromised by diabetic ketoacidosis (DKA), neutropenia, corticosteroid use, and/or increased serum iron. Because of the rising prevalence of these risk factors, the incidence of mucormycosis has risen. Despite disfiguring surgery and aggressive antifungal therapy, the mortality of mucormycosis remains >40%, and approaches 100% in patients with disseminated disease. Clearly new strategies to prevent and treat mucormycosis are needed. Clinical hallmarks of R. oryzae infection include its remarkable angiotropism and the hypersusceptibility of patients with increased available serum iron to this infection. Patients with elevated levels of available serum iron such as those with DKA or who have received deferoxamine are uniquely susceptible to mucormycosis, but not other fungal infections. Deferoxamine acts as a xeno-siderophore which supplies previously unavailable iron to the fungus. We have shown that iron chelation with chelators that are not utilized by the fungus to obtain iron protects mice from infection with R. oryzae. We also found that the high affinity iron permease (Ftr1p) is critical to the ability of the fungus to obtain iron during infection. Equally important is our recent identification of the iron-regulated GRP78 as a host cell receptor to which R. oryzae binds during the process of invading endothelial cells, a step required for angioinvasion. Finally, we found that anti-Ftr1p or anti-Grp78 antibodies markedly, but not completely, protected DKA mice from infection with R. oryzae. These findings underscore the critical role of iron and invasion of vascular endothelial cells in the organism's virulence strategies. We propose to build on these exciting data to further characterize fungal and host targets that are involved in iron uptake and/or regulated by iron. Our goal is to develop multiple immunotherapeutic strategies that will prove to be synergistic in preventing and/or treating lethal mucormycosis. We will achieve this goal by identifying the fungal ligand involved in mediating binding of R. oryzae to endothelial cell GRP78. We will continue identifying host receptors, other than GRP78, that promote adherence to and/or invasion of and subsequent injury to endothelial cells by R. oryzae. Additionally, we will study the effect of physiological conditions, including iron, on the pattern of GRP78 expression in vivo. Finally, we will identify fungal receptors which act upstream of Ftr1p in mediating iron uptake from the host. Achieving these specific aims will further define the role of iron in the establishment and progression of mucormycosis and define possible novel therapeutic strategies that can be applied concurrently against the disease.